Production of 1,3 dimethyl-4-phenyl-4-hydroxy-piperidine



Patented Feb. 21, 1950 PRODUCTION OF 1,3 DIMETHYL- l-PHENYL- l -HYDROXY-PIPERIDINE John Lee, Essex Fells, and Leo Berger, Nutley, N. J., assignors to Hofimann-La Roche Inc., Nutley, N. J., a corporation of New Jersey N Drawing. Application July 8, 1946,

Serial No. 682,134

1 Claim. 1

The present invention relates to N-tertiary piperidine compounds and to a process for producing them.

1 alkyl l acyloxy 4 aryl piperidines have heretofore been prepared by reacting l-alkyllpiperidone with Grignard reagents as, for example, ArMgHal to form the Grignard complex which is decomposed with water to form the corresponding 1-alkyl-l-aryl-4-hydroxy piperidines which are then acylated, as described by Jensen and Lundquist (Dansk. Tidsskr. Farm., 17 1T3-82 [1943]) and in Danish Patent No. 60,592, published February 15, 1943.

It has now been found that these and other new l-organically substituted-4-piperidinols and ie-organically substituted-4-acyloXy piperidines which can be represented by the following general formula:

where R stands for an N-tertiary piperidine residue in which the N-substituent can be an alkyl, such as methyl and branched alkyl, such as isopropyl, substituted alkyl as, for example, methoxyethyl, alkaryl such as benzyl, or cycloalkyl such as cyclohexyl; R. stands for a substituent such as an alkyl, aryl, aralkyl, heterocyclyl, heterocyclyl-methyl radical and the like; and X stands for hydrogen or acyl as, for example, acetyl, propionyl, butyrl, succinoyl, benzoyl, furoyl and the like can be more advantageously prepared by reacting lithium-organic compounds, such as lithium-alkyls, lithium-aryls, lithium-heterocyclyls, and the like with N-tertiaryl-piperidones.

The reaction proceeds smoothly and with a considerable increase in yields as compared with the employment of Grignard reagents on 4- piperidones. Not only are the yields obtained larger when employing the lithium organic compounds, but by the employment of this type of lithium reagent, the preparation of new oxylithium piperidine compounds or complexes can be effected. The complexes can be represented by the following formula:

where R and R have the same significance as in Formula I.

The large increase in yields obtained when employing the lithium organic compounds in the reaction as compared with the Grignard reagent is strikingly illustrated in the case where l-butylpiperidone is employed as a starting material. Thus, when phenyl magnesium halide is reacted with l-butyl-piperidone under various conditions of temperature, solvent, and concentration of reactants, a yield of 25-30 per cent of l-butyllphenyl-4-hydroxy-p-iperidine is obtained on decomposition ofthe Grignard complex. On the other hand, when lithium-phenyl is reacted with the same piperidone, and the lithium complex hydrolyzed a yield of overv per cent of the piperidinol is attained.

Piperidinols of Formula I where X is H are readily formed from the lithium complex obtained on reacting the piperidone with the lithium compound by decomposing the complex with water which may be made slightly acid or alkaline to facilitate the conversion. The l-piperidinol can be readily isolated, and acylated.

A particular advantageof the new process is that instead of decomposing the 4-oxylithium piperidine complex to form the 4-piperidinol, it can be directly acylated without the intermediate hydrolysis of the complex to the piperidinol, and the 4-acyloxy piperidine compounds obtained directly. This direct method of acylating the lithium complex offers the important advantage that it eliminates several manipulations, isolation and purification of the intermediate piperidinol, thus considerably reducing the cost of preparing the compounds of the above formula.

Another advantage of the employment of the lithium organic compounds in the reaction in place of Grignard reagents is that it permits the introduction in the 4-position of the piperidine compound of substituents which were extremely diflicult of access or entirely inaccessible in the form of a Grignard reagent, such as, for example, a pyridyl or picolyl radical; or which could not be brought to react with the piperidones as, for example, thienyl magnesium halides.

The lithium compounds which are employed in the reaction with the piperidones may be represented by the following formula: R'Li, wherein R stands for a lower alkyl, aralkyl, aryl, heterocyclyl, or heterocyclomethyl radical and the like.

When these are reacted with the piperidones, the resulting lithium complexes can be represented by the above-mentioned Formula II. These compounds can be isolated from the reaction mixture. In the case of the lower N-alkyl substituents, the complexes are insoluble and can be removed, taking precautions to work under a nonreactive atmosphere, such as dried nitrogen.

example, sodium-phenyl does not .dioxane, isopropyl ether or pyridine.

The complexes may also be soluble in the reaction mixture as in the case of the N-butyl derivatives, in which case, isolation requires the addition of a suitable nonreactive liquid such as large amounts of benzene or removal of the reaction solvent under an anh-ydrous'inert atmosphere. Since the lithium complexes of Formula II are new, these compounds are also included within the scope of our invention.

The RLi compoundswhichare employed in the reaction with the piperidones.are'iprepared by reacting lithium metal with appropriate organic halogen compounds'such .as methyl iodide, butyl chloride, bromobenzene, bromonaphthalene, and the like; or by reacting lithium compounds capable of transferring lithium such..as'='buty1 lithium and phenyl lithium, with appropriate organic compounds such as bromopyridinabromoquinoline, bromocarbazol, and the'like, or by reacting the samelithium compounds capable of transferring lithium with'compounds having an active hydrogen as, for example, 2'-picoline, .2,6-dimethyl pyridine, 'carbazol, dihydroanthracene, dibenzothiophene, furan,'thiophene,and the like.

It has been found thatthe property of reacting with -piperidones is. not exhibitedby other alkali metal derivatives of organic. compounds, as, for

.example, the' sodium derivatives corresponding to the lithium derivatives described above. For react with 1-butyl-piperidone-4 toyield .1-butyl-4-phenyl-4- piperidinol.

The reaction .of the lithium compounds on the piperidones may be carried out in an'inert diluent or solvent such as ether, benzene, .cyclohexane,

The reagents are employed in equivalent amounts, although excess. amounts of one reagent'may be employed where desired. The 4-oxylithium piperidine complexes so obtained may then be hydrolyzed with water rendered slightly acid or alkaline to facilitatethe decomposition and then acylated. It is preferred,.however, to acylate the lithium complex-directly. The reactions involved can be illustrated by the following scheme.

hydrolysy \a\cylation i! 1 \1 the acylatingagent, to have present'an acidbinding' agent-suchas pyridine or potassium carbonate. The acylation may be carriedoutin an "inert solvent as,'for example, acetone 'orbenz'ene. The acyloxy compounds can be converted into the form of-salts, of organicand inorganic acids,

for instance the tartrates, maleates, citrates,

'ethanesulfonates, isethionates, sulfates, .hydrochlorides and thelike.

The -method described herein is particularly "theinvention. 7

EXAMPLE 1 (A) Preparation of 1-is0pr0p1l1Z-4-phenyl- 4-hydrory-pz'peridene In around bottom flask provided with stirrer,

dropping funnel, condenser, and a gas inlet for keeping the system under nitrogen, 200 cc. of

-fluxed for two hours.

dry ether is placed and 4.6 grams of lithium cut .into thinstripsare added. .52 grams of bromobenzene int!) .00. of dry-ether are .addeddropwise and after the addition, themixture.-iszre The ether solution is then cooled to 20 C. and 35 grains of l-isopropyl-piperidone-4 in 35' cc. of dry etherare added dropwise. After atheaddition, .the tem- -perature. is permitted -to.rise to- 0 C. .Dilutehydrochloric acid is added :dropWise until the so- .lution is acid .to Congo :red. The aqueous layer is separatedand loasiiiedwwith 20%--s0dium hydroxide to pH 10. The mixture is-extracted with ether, the ether solution dried/over potassium carbonateand the ether distilled ofi. The residueis dissolved in -75 -cc.--of.hot petroleum ether (B. vP. 3560 0.). The-product, leisopropyllphenyll hydrox'y piperidine, crystallizes out on cooling. M. P. 83 C. On dissolving in etherand passing dry hydrochloric acid gas through the solution, the hydrochloride separates. M. P. 231 C.

(B) Preparation of 1 -isopropyZ4-phenyZ-4- propionomy-piperidz'ne hydrochloride Thirty-two grams. .of l-isopropyl--phenylhydroxy-piperidine is dissolvedin cc. of pyridine, and cc. ofpropionicanhydride is added. .The solution is refluxed for .three hours. .The pyridine and propi'onic .anhydride are distilled off in vacuo and the-residue .basified with 5% sodium hydroxide. ZTheoil isextracted With ether, dried-over potassium carbonateand the ether solution filtered. .Dry hydrochloric acid ,gasis bubbled into the solution. The.hydrochlo- .ride isfiltered o'ff,..dried.in.a.-vacuum desiccator over alkali, .and then. crystallized from acetonemethanol. M. P. 213-4: C.

EXAMPLE 2 Preparation of 4-phenyl-4 hydroacy-I butykpiperidz'ne In "an' apparatus as described in Example 1, are placed 2.l grams-of" lithium strips and 200 ccsof dryether. 23.6-gramsof bromobenzene in dryether-are added slowly and with stirring.

The flask is kept underdrymnitrogen throughout the reaction. A. spontaneous reaction occurs and the ether is refluxed until almost all the lithium is consumed. The flask is then warmed to reflux temperature for /2 hour to complete the reaction.

The flask is cooled with Dry Ice :and acetone 'to -20,;and 15.5:grams of -1-butyl-epiperidone4= in :ether (11:3) careradded slowly. The :reaction ner and Selby (J. A. C. S. 55, 1252 [1933]).

mixture is then stirred for 2-3 hours at '20 C. and the 1-butyl-4-phenyl-4-oxylithium piperidine'complex formed finally decomposedat 20 C. with excess ice and concentrated hydrochloric acid (1:1). An insoluble salt separates. Water is added to dissolve the salt and the ether solution is discarded after being extracted with dilute acid.

The acid solutions are combined and made basic with solid K2CO3 and finally cold NaOI-I to pH 10. A crystalline base separates.

The solid base is filtered through a sintered glass funnel and washed several timeswith coldwater. The product is air-dried and finally dried overnight in vacuo over CaClz.

The aqueous solution of the base is extracted ,with ether several times and the ether solution dried and concentrated to dryness to yield a second crop of crude base. Recrystallized once from petroleum ether, 1-butyl-4-phenyl-4-hydroxy-piperidine, is obtained in pure form. It melts at 86-88 c. It is converted to the hydrochloride and recrystallization from acetone yields a colorless crystalline product which melts at ISO-161 C.

On acylation with acetic anhydride, catalyzed with a drop of concentrated sulfuric acid, l butyl- 4-phenyl4-acetoxy-piperidine hydrochloride is obtained, M. P. 207-208 C.

On treatment with propionic anhydride, 1,- butyl-4-phenyl-4-propionoxy-piperidine hydrochloride is obtained, M. P. 204-206 C.

EXAMPLE 3 Preparation of 4-(3-pyridyl) -4-hydrozry- I-butyZ-piperz'dz'ne Thirty-nine grams of butyl chloride are re acted with lithium according to Gilman, Zoeillbutyl lithium solution is cooled to 40 C. in

an apparatus asdescribed in Example 1, and 50 I grams of 3-bromopyr'idine in dry ether are added dropwise. An instantaneous reaction occurs, forming .a brown complex which is stirred at 40 C. for minutes. I 15.5 grams of l-butyl- 4-piperidone'in dry ether are then slowly added I atthis temperature and on completion of the crystallized In a similar manner to Example 3, butyl lithium prepared from 13.0 grams of butyl chloride and 2.0grams or" lithium are reacted with 15.5 grams of l-butyl-piperidone-l. 14.4 grams of a thick syrup, boiling at 115-118/l mm. are obtained. The syrup crystallizes spontaneously on standing overnight. The base is very low melting and cannot be recrystallized.

Converted to the hydrochloride by dissolving in ether and passing dry hydrochloride acid gas through, a shiny papery product, 4-n-butyl-4- hydroxy-l-butyl piperidine hydrochloride, is obtained which when recrystallized from ethyl acetate-methanol melts at 147-148 C.

By acylating the l-butyl-4-n-butyl-4-hydroxy piperidine hydrochloride with acetic anhydride, 1-butyl-4-n-butyl-4 acetoxy piperidine hydrochloride, M. P. 229-230 0., when crystallized from ethyl acetate-methanol, is obtained. 7

Similarly, by acylating with propionic acid anhydride, 1-butyl-4-butyl-4-propionoxy-piperidine hydrochloride, M. P. 218-219" 0., when from ethyl acetate-methanol, is obtained. I EXAMPLE 5 Preparation of 4-(2-pic0lyl) -4-hydro.ry1 [butyl-piperidine Phenyl lithium prepared from 28 grams of boils at 148-150 C./0.9 mm. The compound is 4- (2-picolyl) -4-hydroxy-l-butylpiperidine.

addition, the temperature is allowed to rise to ,15 C. After stirring for minutes at this temperature, the reaction mixture is decomposed by pouring in a mixture of ice and hydrochloric acid. The ethereal solution is separated, extracted with ,a little dilute hydrochloric acid and the acid solution returned to the reaction mixture. This is then basified with cold 10% NaOH solution to pH 10 and extracted with ether.

I After drying the ether extract and removal of the solvent, a viscous yellow syrup remains which distills at 156-168 C. at 0.5 mm. On distillation, the distillate crystallizes spontaneously and can be recrystallized from hexane, yielding 4-(3- pyridyl) -4 hydroxy 1 butyl piperidine, M. P. 80-81 C. y

This product yields, upon acetylating with acetic anhydride or acetyl chloride and subsequent treatment with hydrogen chloride, 4-(3- pyridyl) -4-acetoxy 1 butyl piperidine hydrochloride melting at 215-216 C. when crystallized from ethyl acetate-methanol.

When propionic anhydride or propionyl chloride is employed as the acylating agent, 4-(3- pyridyl) -4-propionoxy-l-butyl-piperidine hydrochloride melting at 198-199 C. when crystallized from ethyl acetate-methanol, is obtained.

On acylation with acetic anhydride and propionic anhydride and subsequent transformation to the hydrochloride, it yields 4-(2-picolyl)-4- acetoxy-l-butyl-piperidine hydrochloride which is a hygroscopic amorphous glass, and 4-(2-picolyl) -4-propionoxy-l butyl piperidine hydrochloride which is also a hygroscopic amorphous glass.

, EXAMPLE 6 Preparation of 4-(2-pyridyl) -4- hydroxy-1- butyl-piperidine Thirty-nine grams of butyl chloride is reacted with 6 grams of lithium as described at room temperature during a period of four hours. At this time the lithium has completely reacted and is cooled to -45 C. and 50 grams of 2-bromopyridine dissolved in ether are added rapidly. The reaction proceeds smoothly and the color changes from colorless to a deep red-violet. After stirring at -45 C. for 20 minutes, 15.5 grams of 4-butyl-piperidone-4 are added dropwise. at 15 C. and the lithium complex decomposed by pouring into ice and hydrochloric acid and working up in the manner described. In this way, a clear viscous syrup is obtained boiling at 147/1 mm. This product, 4-(2-pyridyD-4- hydroxy-l-butyl-piperidine, does not crystallize. On propionylation and transformation into the dihydrochloride, 4- (Z-pyridyl) -4-propionoxy-1- The solution is then stirred for one hour Preparation of ,4- (Z-jarylj '-'.4-hydroa:y-l-batyl- Phenyl-lithiun isgprepared from: 5.0 grams of ,lithium and-AQgrains; oflbrornobenzenein 200cc.

7 of ether. To'this, at C., 13.4 grams-of 2,6-

lutidine in ether are added in:.-20--minutes. The

qlpurplish-colored solution is acooled to .30- C. and i3l,grams..of lebutyll piperidone .in-..etlie.lz .is added slowly. The. color changes from purple I to deep Burgundy-red and :becomes clear. After v-a further; hour at 20 C. it is decomposed -with -a mixture :of equal parts of concentrated hydrochloric .acid and ice. "The aqueous-soluation .is -separated I and alkalinized, and-extracted with ether. The ether solution isdriedoveranhydrous potassiumgcarbonate for 24,-hours,; filtered. and .the -solvent removed. vvThe residue,

fractionated at 1 mm., yieldsa producttof the, abovementioned structure, boiling at Bil-142 C."

The hydrochloric acid salt. lis laijligh-t yellow, hygroscopic,- amorphous dihydrochloride. containh1g4 M. of water of crystallization.

On acylation with 1propionic anhydride-.and a "a .trace'of' H2SO4 and with subsequent formation a of the hydrochloride, .4-propionoxy-4- (.6' -methyl- 2'-picolyl)-l-butyl-piperidine dihydrochloride is obtained as a glassy'product.

Similarly on acylation with acetic anhydride and. salt iformation, -.4-acet0Xy-'4- (6 -methyl-2' picolyl) -1butyl piperidine dihydrochloride is obtained as a glass.

EXAMPLE 8 .piperidz'ne i -Five grams' oflithium and 52.5' grams of "bromovbenzene'are 'reacted'to form ,phenyl lithium in 3250 cc. ofether. .1'7'.03grams of freshly-distilled furan-in-ZO cc. of-ether are added "dropwise at reg ae-s 'on propionylation :and, subsequent .z format-ion of :the hydrochloride, d-methyl-4-propionoxy-1- room "temperature and themixture-refluxed for,

three hours. The mixture lSthEIlCQOlBdtO .10

C. and 15.5 grams of 1-butyl-piperidone-4 are added-slowly. It'is stirred at -1'5:C-."for one hour and then-decomposed with hydrochloric acid andicexmixture. "On working uprin the manner-described, a product of the "above strucobtained. Thisis converted to the hydrochloride by dissolving in dry ether and passing through hydrochloric acid gas. The product-is -anz-amorphous glass. V

When acylated with propionic anhydride in thepresence of a drop of sulfuric-acid,- a pro- -pionate is'obtained which on conversion to'the not, 4- (Z-furyl) -4-propionoxy-l-butyl piperidine hydrochloride. v

Preparation of 4-methyZ-4-hydroxy-I-batylpiperidine -'28.0. grams of freshly distilled methyl iodide ''-and 2.8-grams of freshly :cutdithium metal are reacted in 200 cc. of ether. I .The reaction is complete in .two hours. .The mixtureis themcooled to -.15' C. and15.5 grams of.-1--buty1=piperidone-4 .in ether .are added dropwise. Afterstirlfing for one hour; at this temperature, the :mixture is .de-

:-:composed .with, rice and hydrochloric acid. and .Workedup inthe-manner. described. The-product 'i'obtained, fractionated at-1 .0.mm syields'an: oil

boiling at 75- 76 C. n =1e4686. 'I he productais ;butyl-,.pip.eridine :hydrochloride .is' obtained, melting at. 226-.-227 .5 1C., When crystallized fromethyl racetate -methanol j mixture. I v

EXAMPLElO Preparation:

- grams of 'l-butyl piperidone-4 in etheris-then addedidropwisejand the mixture stirred at this temperature for one hour. The reactionproduct is'then decomposed with -ice and hydrochloric acid. and worked up in the manner described, I when a'IDIOdLlCtOf the above-mentioned structure .boiling at 134.'135C;/ 1-2 mm., is obtained. This material crystallizes spontaneously. On acylation withpropionic anhydride in dle-presence of a trace of sulfuric acid, a product is obtained which on solution 'inether'and precipitation with hydrochloric acid "yields 4-hexyl-4 -propionoxyl-butyl-piperidine hydrochloride which on 'crystallization from ethyl acetate melts'at 210-211? C.

Preparation of 4-.( -2-.thicayl) -4-hydroxy-1-batylpiperidine I 52.5--grams of =bromobenzenedand15 grams of lithium are reacted in250-cc. of ether and at the end of three hours, 21.0 grams of thiophene mixed with 25; cc. "of ether are added -'dropwise. The mixture-is-refluxed for 2 hours and then-cooled J" to --,2 0*C. and l5.5 grams-of l-butyl-piperidone- 4in etheraread'ded during hour. 'The'tem- Hperatureis allowed'to rise to room temperature -and-kepttherefor 20hours. f-"It isthen decomposed with hydrochloric acid and ice and :wor-ked upinthe manner described. The residuecrystallizesand on recrystallization :from hexane, yieldsthe above=mentioned product, melting at -'-82-'83' C. When -transformed to the hydrochlohydrochloride formsan amorphous glassy prodride, the compound-yields a monohydrochloride, M."P;"168l69 -C.

fI-he free base Whenreacted with propionic an- '*hydride.and then transformed to #the hydrochlo- -ride yields a colorless :crystalline product, fi l- (2- 7 th-ienyl-)'--4-propionoxy l butyl piperidine :hydrochloride, melting; -at 151453 '0.

.1 -.-;2EXAMPLE 12 Preparation of 1=,-3-dimethyl-4 phenyle4 hydrowy- "piperiidz'ne .Phenyl ,lithium' is iormed by reacting 1.4. grams '.of, lithium. and'l6.0.-grams oibromobenzene in .100

cc. of tether.v Thesolutioniscooled to ,20 C.,

and to this a solution of 12:7 grams of 1,3 dimeth- ;yl-4..piperidone .in..ether isadded dropwise with .stirring. JAitertheaddition, thestirring is con- 1 .tinuedior, a. further two hours at -.-:20 C. andthe .reactionm'ixture is then decomposed with icejand .hydrochloric acid mixture. Theacidified layer is w er dryingtheethensolutionandremoval of the ,S'O .Vnt,-the.]feSi-d1le on. distillation.- in vacuum. dis- ,tillsch iefiyat .15.5- .C./-l0,mm.,,yielding a product .ci-theaboveementionedstructure which on-crystallizationfrom n-hex-anemelts at 1029 C.

separated, basifledandextractedwith ether. ,Aft-

EXAMPLE 13 Preparation of 1-methyl-3,5-diethyZ-4-phenyZ-4- hydroxy-piperz'dine 1.26 grams of lithium are reacted with 14.1 grams of bromobenzene and 100 cc. of ether at room temperature. The mixture is then cooled to,-20 C. and 10 grams of 1-methyl3,5-diethy1- 4 -pip'eridone in ether are added dropwise during Ehour. After stirring for two hours at this temperature, the mixture is decomposed with hydrochloric acid and ice and worked up in the manner described. This yields 7 grams of a product of the above-mentioned structure which crystallized from normal hexane, M. P. 137-140 C.

grams of the compound are refluxed with 5 cc. of propionyl chloride on a steam bath for three hours. The excess propionyl chloride is removed in vacuum, water added, and the mixture basified with sodium hydroxide solution. The propionylated base is extracted with ether and transformed to the hydrochloride which on re crystallization from acetone melts at 216 C. The

product obtained is 1-methy1-3,5-diethyl-4-phenyl-4-propionoxy-piperidine hydrochloride.

In the above examples the 4-oxylithium piperidine complexes formed by the reaction of the organo-lithium compounds on the piperidones are decomposed to the corresponding piperidinol which is subsequently acylated. The following examples will serve to illustrate the process wherein the lithium piperidine complex is directly acylated without the intermediate hydrolysis to the piperidinol and subsequent acylation.

EXAMPLE 14 Preparation of 1-isopropyl-4-phenyl-4-acetorypiperz'dine hydrochloride removed by allowing the temperature to rise to -.55 56. An additional 100 cc. of benzol is then added. The reaction is then cooled to 0 C. and 100 cc. of acetic anhydride in 200 cc. dried benzol is added. A yellowish-green precipitate forms, forming a thick mixture which after dilution of a further liter of benzene is refluxed for 30 minutes and allowed to stand overnight. The mixture is then cooled to 0 C. and decomposed with insoluble hydrochloride which separates is redissolved by the addition of 4 liters of water and the 100 cc. of water and finally 100 cc. of hydrochloric 1 acid mixed with 100grams of ice are added. The

mixture is extracted with ether, the ether layer is discarded, the aqueous solution is basified to pH 10 with sodium hydroxide solution and extracted with ether. The ether solution is dried with sodium sulfate, the ether removed and the residue fractionated when 52.5 grams of a product boiling at 1419-151 C./3-4 mm. are obtained. The 1-isopropyl-4-phenyl-4-acetoxy piperidine crystallizes from low boiling benzene (30-60) and melts at -76. It yields a hydrochloride which on crystallization from acetone-methanol, melts at 205-6" C.

EXAMPLE 15 Preparation of 1-isopropyl-4-phenyl-4-proptonoaty-piperidine In a manner similar to Example 14, lithium complex is formed from the same amounts of phenyl lithium and 1-iS0pr0pyl-4-piperidone and the reaction mixture is reacted with cc. of propionic anhydride in 250 cc. of benzol, the reaction mixture refluxed for 30-40 minutes and then worked up in the manner described in EXa-mple 1. On fractionation, 27.0 grams of l-isopropyl-lphenyl-l-propionoxy piperidine, B. P. -142/ 1-2 mm. are obtained. When transferred to the hydrochloride, on crystallization from isopropyl alcohol, this salt melts at 208209 C.

The above procedure as illustrated by Examples 14 and 15 involving the direct acylation of the piperidine lithium complex can be applied to the production of the 4-acyloxy compounds as described in Examples 1-13 and in general, to the broad class of piperidine lithium complexes 01' Formula II.

We claim:

Process of preparing 1,3-dimethyl-4-phenyl-4- hydroxy-piperidine which comprises reacting un der anhydrous conditions phenyl lithium with 1,3-dimethyl-4-piperidone and hydrolyzing to produce 1,3-dimethyl-4-phenyl-4-hydroxy-piper idine.

JOHN LEE. LEO BERGER.

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